Abstract 3475: RMC-9805, a first-in-class, mutant-selective, covalent and orally bioavailable KRASG12D(ON) inhibitor, promotes cancer-associated neoantigen recognition and synergizes with immunotherapy in preclinical models
Authors: Marie J. Menard, Christopher Chow, Kevin Chen, Cristina Blaj, Nataliya Tovbis Shifrin, Haley Courtney, Nicole M. Nasholm, Anna Pham, Alice Kumamoto, Swetha Ganesh, James W. Evans, Lindsey Lawrence, Brian Vonmelchert, Amy C. Kwok-Parkhill, Jingjing Jiang, John E. Knox, Jacqueline Smith, Elsa Quintana
Journal: Cancer Research (2023)

Abstract Major epithelial tumors harboring the cancer driver KRASG12D, the most common oncogenic KRAS mutation1, remain an outstanding unmet medical need. While oncogenic RAS primarily promotes tumor progression through sustained cellular proliferation, there is also increasing evidence that it adversely shapes the tumor microenvironment (TME) through the induction of immuno-suppressive cytokines2, downregulation of MHCI, and modulation of checkpoint proteins3. KRASG12D oncoproteins can be selectively targeted with the covalent tri-complex RAS(ON) inhibitor, RMC-9805, which has been shown to inhibit RAS signaling in KRASG12D mutant cancer cells and induce apoptosis. RMC-9805 also decreased the secretion of immunosuppressive cytokines by KRASG12D tumor cells, while promoting the secretion of lymphocyte-recruiting factors. Oral administration of RMC-9805 drove durable complete responses and synergized with anti-PD-1 in an immune-infiltrated colorectal KRASG12D mutant model. Re-challenge experiments further demonstrated that RMC-9805 induced immunological memory. The activity of RMC-9805 was also assessed in an orthotopic, immune-evasive, GEMM-derived preclinical model for PDAC, where it induced a profound and sustained inhibition of RAS signaling, driving initial tumor regressions and significantly prolonging survival. Tumors treated with RMC-9805 in vivo showed significant transformation of the TME in favor of anti-tumor immunity, with an increase in T cell infiltration and decrease in immunosuppressive myeloid cells, including M2-like macrophages and MDSCs. RMC-9805 also modulated expression of cancer cell surface proteins, notably decreasing expression of immune checkpoint molecules while significantly increasing MHC-I expression. TCR sequencing of T cells from tumors and blood harvested from treated mice revealed a significant increase in T cell diversity, as well as an increase in the number of shared TCR clones among all KRASG12D(ON) inhibitor-treated samples, suggesting cancer-associated antigen recognition. Overall, in these preclinical experiments, RMC-9805 exhibited direct anti-tumor effects and indirectly transformed the TME through inhibition of cancer cell-intrinsic KRASG12D oncogenic signaling. The increased antigen presentation, recognition, and T cell infiltration induced by inhibition of mutant KRAS may permit a more favorable environment for immune-directed ‘companion’ therapies, such as checkpoint inhibitors, cellular therapies, and/or vaccines. [1] Timar, J. et al, 2020 [2] Hamarsheh, S. et al, 2020 [3] Sumimoto, H. et al, 2016 Citation Format: Marie J. Menard, Christopher Chow, Kevin Chen, Cristina Blaj, Nataliya Tovbis Shifrin, Haley Courtney, Nicole M. Nasholm, Anna Pham, Alice Kumamoto, Swetha Ganesh, James W. Evans, Lindsey Lawrence, Brian Vonmelchert, Amy C. Kwok-Parkhill, Jingjing Jiang, John E. Knox, Jacqueline Smith, Elsa Quintana. RMC-9805, a first-in-class, mutant-selective, covalent and orally bioavailable KRASG12D(ON) inhibitor, promotes cancer-associated neoantigen recognition and synergizes with immunotherapy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3475.